Highlights
This study introduces a comprehensive framework for understanding heart failure with preserved ejection fraction (HFpEF) pathophysiology through exercise physiology and metabolomics. The research demonstrates that multi-organ exercise deficits serve as powerful predictors of HFpEF development and prognosis, with significant implications for early identification and personalized therapeutic targeting.
• Patients presenting with five or more exercise deficits face nearly four-fold increased hazard of cardiovascular events or mortality (HR 3.90, 95% CI 1.74-8.75, P<0.0001)
• Metabolite signatures associated with elevated pulmonary capillary wedge pressure/cardiac output slope confer 43% increased risk of incident heart failure per standard deviation (HR 1.43, 95% CI 1.20-1.71, P<0.001)
• Integration of all exercise deficit metabolic signatures achieves approximately 20% net reclassification improvement over conventional HFpEF risk factors
• Genetic analyses reveal shared predisposition between HFpEF and its cardiometabolic comorbidities, suggesting common underlying mechanisms
Background: The Clinical Challenge of HFpEF
Heart failure with preserved ejection fraction represents one of the most challenging syndromes in contemporary cardiovascular medicine. Unlike heart failure with reduced ejection fraction, HFpEF is characterized by normal systolic function yet symptomatic exercise intolerance, frequently accompanied by multiple comorbidities including obesity, hypertension, diabetes, and chronic kidney disease. Despite increasing prevalence, HFpEF has historically lacked effective therapeutic interventions, largely due to heterogeneous pathophysiology and limited understanding of disease mechanisms.
Exercise intolerance serves as the hallmark manifestation of HFpEF, yet the underlying contributors to this limitation remain incompletely characterized. The traditional paradigm has focused on cardiac-specific abnormalities, but emerging evidence suggests that HFpEF involves dysfunction across multiple organ systems. This study by Landsteiner and colleagues addresses this knowledge gap by employing comprehensive physiologic testing, advanced metabolomic profiling, and genomic analysis to characterize the multi-organ basis of exercise limitation in HFpEF.
Study Design and Methods
The investigative team conducted a sophisticated translational study integrating three complementary approaches to characterize HFpEF pathophysiology. The primary cohort included HFpEF patients who underwent invasive cardiopulmonary exercise testing (iCPET), enabling simultaneous assessment of cardiac, pulmonary, and peripheral vascular responses to exertion.
The study systematically evaluated seven distinct exercise physiologic deficits: reduced exercise stroke volume and heart rate response, steep pulmonary capillary wedge pressure/cardiac output (PCWP/CO) slope indicating impaired cardiac compliance, elevated pulmonary vascular resistance, pulmonary mechanical limitation to exercise, impaired peripheral oxygen extraction, and obesity-related exaggerated metabolic cost of exercise initiation. This comprehensive phenotyping enabled detailed mapping of the distribution and functional significance of each deficit.
For metabolomic analysis, the researchers applied LASSO regression to identify metabolite signatures associated with each exercise deficit. These signatures were then validated in 6,345 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) with approximately 20 years of follow-up, examining relationships with clinical-demographic features, cardiac magnetic resonance imaging findings, and incident heart failure events.
The genomic component involved mapping deficit-implicated metabolites to tissue-specific genetic variation in approximately 2 million individuals with heart failure, as well as the largest genome-wide association studies of HFpEF comorbidities including obesity, renal disease, and diabetes. This approach enabled evaluation of shared metabolic mechanisms underlying HFpEF pathophysiology and its associated conditions.
Key Findings
The iCPET cohort demonstrated marked heterogeneity in exercise responses, with a mean age of 61.7±14.1 years, 54% female participants, and mean BMI of 30.6±6.7 kg/m² reflecting the typical HFpEF phenotype. Patients exhibited a broad spectrum of compound cardiac and extra-cardiac exercise deficits, confirming the multi-organ nature of HFpEF pathophysiology.
The prognostic significance of exercise deficits emerged clearly: individuals presenting with five or more deficits demonstrated dramatically elevated risk. The hazard ratio for incident cardiovascular event or mortality reached 3.90 (95% CI 1.74-8.75, P<0.0001), representing nearly four-fold increased risk compared to those with fewer deficits. This dose-response relationship between deficit burden and adverse outcomes underscores the cumulative impact of multi-organ dysfunction.
Metabolite profiling revealed distinct signatures associated with specific exercise deficits. The metabolite signature corresponding to exercise PCWP/CO slope emerged as particularly prognostic, conferring a hazard ratio of 1.43 per standard deviation increment (95% CI 1.20-1.71, P<0.001) for incident heart failure in the MESA cohort. This finding suggests that circulating metabolites may serve as accessible biomarkers reflecting underlying cardiac pathophysiology.
Perhaps most clinically relevant, integration of all iCPET deficit metabolic signatures into a single predictive model yielded approximately 20% continuous net reclassification improvement over traditional HFpEF risk factors. This substantial improvement in risk prediction demonstrates the incremental value of multi-organ physiologic assessment combined with metabolomic profiling.
The genomic analyses revealed compelling evidence of shared genetic predisposition. Genes implicated by the exercise deficit metabolome demonstrated enrichment in the heart failure genome-wide association study of approximately 2 million individuals. Furthermore, these genes showed significant overlap with genetic variants associated with obesity, renal dysfunction, and diabetes. This pattern suggests that HFpEF and its comorbidities share fundamental metabolic mechanisms operating throughout the lifespan, rather than representing independent disease processes.
Mechanistic Insights and Clinical Implications
These findings carry substantial implications for understanding HFpEF pathophysiology and developing therapeutic strategies. The identification of seven distinct exercise deficits challenges the traditional single-organ focus and supports a systems biology approach to HFpEF. Organ-specific responses to exercise—including cardiac, pulmonary, vascular, and peripheral muscle components—each contribute independently to exercise intolerance and prognosis.
The metabolomic signatures provide mechanistic insights into these physiologic deficits. Metabolites associated with elevated PCWP/CO slope likely reflect abnormalities in cardiac energy metabolism, substrate utilization, and systemic inflammation. The observed associations with obesity-related metabolic cost of exercise initiation suggest that adipose tissue dysfunction and systemic inflammation may mechanistically link obesity to exercise intolerance in HFpEF.
The genomic findings of shared genetic architecture between HFpEF and its comorbidities have particularly important implications. Rather than viewing HFpEF as an isolated cardiac condition, these results position HFpEF within a spectrum of cardiometabolic disorders sharing common genetic and metabolic determinants. This perspective suggests that therapeutic approaches targeting metabolic pathways—rather than cardiac function alone—may prove more effective.
From a clinical perspective, the nearly 20% net reclassification improvement indicates that metabolomic profiling of exercise deficit signatures could substantially enhance risk stratification. Current HFpEF diagnosis relies heavily on symptoms and ejection fraction, which may miss early disease or fail to identify those at highest risk. Integration of metabolite signatures could enable earlier identification of at-risk individuals and guide preventive interventions.
Study Limitations and Future Directions
Several limitations merit consideration when interpreting these findings. The iCPET cohort, while comprehensively characterized, represented a relatively selected population referred for specialized testing, potentially limiting generalizability. The MESA cohort, while large and diverse, involved community-dwelling individuals who may differ from clinical HFpEF populations. Additionally, the observational nature of the study limits causal inference regarding metabolite-disease relationships.
Future research should validate these findings in independent cohorts and examine whether targeting the identified metabolic pathways can modify disease progression. Intervention studies targeting specific deficit patterns—such as pulmonary rehabilitation for those with mechanical limitation or metabolic modulators for those with impaired peripheral extraction—could establish therapeutic relevance of this phenotyping framework.
Conclusion
This landmark study establishes exercise-induced multi-organ physiologic deficits as powerful predictors of HFpEF development and prognosis. Through integration of invasive cardiopulmonary testing, metabolomics, and genomics, researchers have demonstrated that the burden of exercise deficits—rather than any single abnormality—drives adverse outcomes. The identification of metabolite signatures with independent prognostic value, combined with evidence of shared genetic architecture with cardiometabolic comorbidities, provides a foundation for precision medicine approaches to HFpEF.
These findings represent a paradigm shift from viewing HFpEF as primarily a cardiac disorder toward understanding it as a multi-system condition with metabolic underpinnings shared with obesity, diabetes, and renal disease. This reconceptualization opens new avenues for prevention, early detection, and targeted therapy. As the search for effective HFpEF treatments continues, approaches addressing the multi-organ nature of exercise limitation and the metabolic pathways linking HFpEF to its comorbidities may prove most successful.
Funding
This study was supported by the National Heart, Lung, and Blood Institute and other institutional research grants. The Multi-Ethnic Study of Atherosclerosis was conducted under NHLBI contracts and supported by numerous research institutions.
References
Landsteiner I, Stolze LK, Peterson TE, et al. Multi-Organ Physiologic Deficits During Exercise Identify Clinical and Molecular Predisposition to Heart Failure with Preserved Ejection Fraction. Circulation. 2026 Apr 7. PMID: 41944041.
